Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

Patrycja Puchalska, Shannon E. Martin, Xiaojing Huang, Justin E. Lengfeld, Bence Daniel, Mark J. Graham, Xianlin Han, Laszlo Nagy, Gary J. Patti, Peter A. Crawford

Research output: Contribution to journalArticle

Abstract

Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

Original languageEnglish (US)
Pages (from-to)383-398.e7
JournalCell Metabolism
Volume29
Issue number2
DOIs
StatePublished - Feb 5 2019

Fingerprint

Hepatocytes
Fibrosis
Macrophages
Coenzyme A-Transferases
Keto Acids
Liver
Enzymes and Coenzymes
Hydroxybutyrates
Glucose
Ketone Bodies
Metabolomics
Metabolome
Glycosaminoglycans
Ketones
Isotopes
acetoacetic acid
Mass Spectrometry
Carbon
Diet
Wounds and Injuries

Keywords

  • acetoacetate
  • beta-hydroxybutyrate
  • fibrosis
  • immunometabolism
  • ketone bodies
  • macrophages
  • nonalcoholic fatty liver disease
  • stable isotope tracing untargeted metabolomics

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Puchalska, P., Martin, S. E., Huang, X., Lengfeld, J. E., Daniel, B., Graham, M. J., ... Crawford, P. A. (2019). Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis. Cell Metabolism, 29(2), 383-398.e7. https://doi.org/10.1016/j.cmet.2018.10.015

Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis. / Puchalska, Patrycja; Martin, Shannon E.; Huang, Xiaojing; Lengfeld, Justin E.; Daniel, Bence; Graham, Mark J.; Han, Xianlin; Nagy, Laszlo; Patti, Gary J.; Crawford, Peter A.

In: Cell Metabolism, Vol. 29, No. 2, 05.02.2019, p. 383-398.e7.

Research output: Contribution to journalArticle

Puchalska, P, Martin, SE, Huang, X, Lengfeld, JE, Daniel, B, Graham, MJ, Han, X, Nagy, L, Patti, GJ & Crawford, PA 2019, 'Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis', Cell Metabolism, vol. 29, no. 2, pp. 383-398.e7. https://doi.org/10.1016/j.cmet.2018.10.015
Puchalska P, Martin SE, Huang X, Lengfeld JE, Daniel B, Graham MJ et al. Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis. Cell Metabolism. 2019 Feb 5;29(2):383-398.e7. https://doi.org/10.1016/j.cmet.2018.10.015
Puchalska, Patrycja ; Martin, Shannon E. ; Huang, Xiaojing ; Lengfeld, Justin E. ; Daniel, Bence ; Graham, Mark J. ; Han, Xianlin ; Nagy, Laszlo ; Patti, Gary J. ; Crawford, Peter A. / Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis. In: Cell Metabolism. 2019 ; Vol. 29, No. 2. pp. 383-398.e7.
@article{25d206c614ce4ad29270b575d87f76d9,
title = "Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis",
abstract = "Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15{\%} of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.",
keywords = "acetoacetate, beta-hydroxybutyrate, fibrosis, immunometabolism, ketone bodies, macrophages, nonalcoholic fatty liver disease, stable isotope tracing untargeted metabolomics",
author = "Patrycja Puchalska and Martin, {Shannon E.} and Xiaojing Huang and Lengfeld, {Justin E.} and Bence Daniel and Graham, {Mark J.} and Xianlin Han and Laszlo Nagy and Patti, {Gary J.} and Crawford, {Peter A.}",
year = "2019",
month = "2",
day = "5",
doi = "10.1016/j.cmet.2018.10.015",
language = "English (US)",
volume = "29",
pages = "383--398.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

AU - Puchalska, Patrycja

AU - Martin, Shannon E.

AU - Huang, Xiaojing

AU - Lengfeld, Justin E.

AU - Daniel, Bence

AU - Graham, Mark J.

AU - Han, Xianlin

AU - Nagy, Laszlo

AU - Patti, Gary J.

AU - Crawford, Peter A.

PY - 2019/2/5

Y1 - 2019/2/5

N2 - Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

AB - Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

KW - acetoacetate

KW - beta-hydroxybutyrate

KW - fibrosis

KW - immunometabolism

KW - ketone bodies

KW - macrophages

KW - nonalcoholic fatty liver disease

KW - stable isotope tracing untargeted metabolomics

UR - http://www.scopus.com/inward/record.url?scp=85060728334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060728334&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2018.10.015

DO - 10.1016/j.cmet.2018.10.015

M3 - Article

C2 - 30449686

AN - SCOPUS:85060728334

VL - 29

SP - 383-398.e7

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 2

ER -